Gerald I. Shulman, MD, PhD, MACP, MACE, FRCP, has been awarded the 2021 Manpei Suzuki International Prize for Diabetes Research. The prize recognizes Shulman’s groundbreaking research in the understanding of physiologic regulation of liver and muscle carbohydrate and fat metabolism and its dysregulation in type 2 diabetes (T2D).
Shulman is the George R. Cowgill Professor of Physiological Chemistry, professor of medicine and of cellular & molecular physiology, and co-director of the Yale Diabetes Research Center. He will be presented with the prize during a ceremony in Tokyo on March 11, 2022. The prize is presented annually by the Manpei Suzuki Diabetes Foundation to advance diabetes research for the benefit of people around the world.
We spoke to Shulman about his pioneering research and how it may one day lead to new treatment options for people with type 2 diabetes (T2D).
What sparked your interest and keeps you interested in diabetes?
I first became fascinated by metabolism as a nine-year-old attending a camp for children with type 1 (insulin dependent) diabetes where my father volunteered as the camp doctor. I would watch my fellow campers queue up for their daily injections of insulin, receive their specialized meals, and test their urine for glucose and ketones twice a day. On occasion, I would observe one of them faint from hypoglycemia or be admitted to the camp infirmary for diabetic ketoacidosis.
In medical school I learned about the pandemic of type 2 diabetes (T2D) and its devastating complications, including [blindness, end stage renal disease, and nontraumatic loss of limb]. T2D is also a leading cause of cardiometabolic disease and it is now the leading cause of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) and cirrhosis.
Can you sum up the significance of your research and the paradigm shift it represents?
Insulin resistance is the major factor involved in the pathogenesis of T2D yet the molecular mechanisms responsible for insulin resistance are poorly understood. Insulin resistance is also a major factor in the development of cardiovascular disease and obesity-associated cancers. The relationship between obesity and insulin resistance had been know for many years and my group was able to dissociate obesity from insulin resistance and demonstrate that insulin resistance is not related to how much fat the body has stored but, more importantly, related to the distribution of lipid-derived metabolites inside live and muscle cells that trigger insulin resistance. My lab has gone on to describe the molecular mechanisms by which these lipid-derived metabolites inside the cell triggers insulin resistance, which in turn has led to the development of several new therapies to treat T2D as well as NAFLD/NASH that are now in clinical trials.
How might your findings ultimately be implemented in human beings with diabetes?
One of the new therapies that my group has developed is a controlled released mitochondrial protonophore (CRMP) which promotes increased fat oxidation in the liver and thereby reduces liver fat, liver inflammation and hepatic insulin resistance in rodent models of T2D and NAFLD/NASH. We have recently demonstrated similar safety and efficacy of CRMP in dysmetabolic nonhuman primates and we are now on doing IND-enabling studies to take CRMP and related liver-targeted mitochondrial uncoupling agents to the clinic.
What does the Manpei Suzuki International Prize in Diabetes Research mean to you?
This award highlights and validates the paradigm shifting work that my trainees, colleagues, and I have done at Yale over the last 30 years to understand the pathogenesis of insulin resistance, NAFLD/NASH and cardiometabolic disease. I believe these studies will translate into new therapies and healthier lives for our patients with diabetes, liver disease, and cardiometabolic disease.
Yale’s Section of Endocrinology & Metabolism works to improve the health of individuals with endocrine and metabolic diseases by advancing scientific knowledge; applying new information to patient care; and training the next generation of physicians and scientists to become leaders in the field. To learn more about their work, visit Endocrinology & Metabolism.